The adipoeyte-secreted hormone leptin signals the amount of energy stored in adipose tissue to the central nervous system. We have shown, in the context of this grant, that leptin administration to normalize the relative leptin deficiency induced by short term energy deficiency results in normalization of reproductive and other neuroendocrine defects. We have also shown that altering leptin levels within the normal physiological range, or into supraphysiological levels, has no effect on the same outcomes. Thus, in humans, leptin serves as a critical link between the sufficiency of energy stores and the integrity of the hypothalamic-pituitary- peripheral axes in states of leptin deficiency only. We have subsequently hypothesized that the abnormalities in the reproductive and other neuroendocrine axes in women with hypothalamic amenorrhea (HA), a condition associated with low leptin levels, may also be related to the chronic hypoleptinemia induced by negative energy balance. In a recently completed, open-label, small pilot study using historical controls, we found that leptin replacement to correct the relative leptin deficiency in women with HA resulted in follicular growth and ovulation and significantly improved hormone levels, providing preliminary evidence that leptin may contribute to the etiology of the amenorrhea and that leptin replacement may be a potential treatment for disease states associated with relative leptin deficiency. The goal of this proposal is to confirm and extend these preliminary findings by performing a randomized, double-blinded, placebo-controlled trial of leptin treatment in women with HA and leptin deficiency which would eliminate potential bias and confounding and would verify safety and efficacy of leptin as a new treatment for HA. Since HA accounts for over 30% of amenorrhea in reproductive-aged women and can have significant deleterious effects on fertility, bone health, and overall well-being, this study would have considerable clinical impact if leptin becomes a new, more physiologic, therapeutic option for HA. This is particularly relevant since currently available treatment options for HA have side effects, are not well accepted by some patients, and have suboptimal effectiveness for complications such as osteoporosis. Results of this study will not only help elucidate the pathophysiology of HA but will also provide important new information on leptin physiology in neuroendocrine regulation, bone metabolism and immune function at large, using HA as a model of chronic leptin deficiency. Thus, findings of this study to elucidate leptin physiology may also have applications in the pathophysiology (and possibly therapeutics) of other leptin related diseases, including obesity, a major public health problem.